This proposal will study the role of retinal pigment epithelium (RPE) in the pathogenesis of subretinal neovascularization (SRN), a key process in the exudative form of age-related macular degeneration (ARMD). Two hypotheses will be tested: (1) choroidal endothelial cell (CEC) angiogenesis, which leads to subretinal neovascularization, is modulated by factors expressed by RPE cells and that act on CECs; (2) RPE expression of angiogenesis- modulating factors is influenced by cytokines [tumor necrosis factor- alpha (TNF-alpha), transforming growth factors (TGF-beta)] that are released by activated macrophages. To test these hypotheses, the applicants will test the effects of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor (PAI) and tissue inhibitor of metalloproteinase (TIMP) on human tube-forming CECs in an in vitro angiogenesis model (CECs are grown in a collagen gel where they form a network of tube-like structures that have lumens). The CECs will also be exposed to an overlay of cytokine-activated APE cells or RPE cells genetically-transduced to express angiogenic or antiangiogenic factors. Effects of the designated factors will also be tested in vivo using rabbit and primate models of SAN, by subretinal transplantation of the genetically transduced RPE cells.